Abstract
Mutation A713T in the amyloid precursor protein (APP) has been linked to cases of Alzheimer’s disease (AD), cerebral amyloid angiopathy (CAA) and cerebrovascular disease. Despite its rarity, it has been observed in several families from the same geographical area, in the Calabria region in Southern Italy. Genotyping of 720,000 genome-wide SNPs with the HumanOmniExpress BeadChip was performed for six patients that were representative of apparently unrelated Calabrian families, as well as a Belgian subject of Italian descent (all with the same A713T mutation and disease). Their genomic structure and genetic relationships were analyzed. Demographic reconstruction and coalescent theory were applied to estimate the time of the most recent common ancestor (tMRCA) among patients. Results show that all A713T carriers fell into the genetic variability of Southern Italy and were not more closely related to each other than to any other healthy Calabrian individual. However, five out of seven patients shared a 1.7 Mbp-long DNA segment centered on the A713T mutation, making it possible to estimate a tMRCA for its common origin in the Calabrian region dating back over 1000 years. The analysis of affected individuals with methodologies based on human population genomics thus provides informative insights in support of clinical observations and biomedical research.
Highlights
The analysis looked at genomic regions on chromosome 21 tagging the APPA713T mutation that are shared among the affected subjects, to ascertain the chance that reportedly unrelated individuals belonging to a circumscribed population would share long regions at the disease-causing mutation by common descent
All seven A713T carriers clearly distributed into the Southern Italian clade, as further confirmed by the same principal component analysis (PCA) performed on the obtained coancestry matrix (Figure 1)
As described at the end of this section, by considering the genetic makeup and the genomic relationships of affected individuals carrying peculiar mutations, the analysis of these cases with methodologies based on human population genomics could provide informative insights in support of clinical observations and biomedical research
Summary
Alzheimer’s disease (AD) is the most widespread neurodegenerative disorder, and is primarily characterized by extracellular amyloid plaques, intraneuronal neurofibrillary tangles and synaptic loss [1–3]. Genetics plays a key role in the development of AD, with a heritability estimate between 58–79% and over 90% for late-onset and early-onset AD, respectively [4]. Autosomal dominant familial early-onset AD (Alzheimer’s disease, type 1). Cases are associated with mutations in the gene encoding for the amyloid precursor protein. For some APP mutations the inheritance pattern determines whether AD develops. APPA673T mutation causes earlyonset AD only in the homozygous state, whereas the heterozygous state protects against
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